Role of IL-13 and the IL-13 Associated rs20541 Risk Variant in the Pathogenesis of Psoriasis

 描述（由申请人提供）：银屑病是一种常见的慢性细胞因子驱动的炎症性和过度增殖性皮肤病，与显著的心血管和代谢共病相关。近年来，通过全基因组关联研究（GWAS）在描述银屑病易感遗传危险因素方面取得了重大进展，迄今已确定了41个易感基因座。这些发现的临床重要性是强调， 事实上，几个风险位点指向已经用于治疗银屑病的途径和分子。更重要的是，GWAS的结果有可能确定以前未被重视的途径，这可能是疾病发病机制的关键，因此是理想的治疗靶点。其中一种风险变异位于IL 13基因内，但IL 13基因的作用可能与IL 13基因的表达有关。 13银屑病的发病机制大多不明。然而，一些证据，包括我们自己的初步数据，指向IL-13在银屑病中的主要作用，为我们的假设奠定了基础，即IL-13通过增强Th 1和Th 17诱导的皮肤炎症在银屑病发病机制中具有促炎作用。该提案的目的是确定IL-13在银屑病中的致病作用，阐明所涉及的关键途径和机制，并评估银屑病相关的IL-13 rs 20541风险变体对银屑病皮肤炎症的影响。该项目将提供关于银屑病发病机制中未被重视和研究不足的炎症途径的新数据，它将评估靶向IL-13或其受体系统在银屑病中的潜力，并最终为这种慢性且通常具有破坏性的疾病患者提供更有效的治疗方法。

 DESCRIPTION (provided by applicant): Psoriasis is a common, chronic, cytokine driven inflammatory and hyper-proliferative skin disease associated with significant cardiovascular and metabolic co-morbidities. Major progress has been made in recent years delineating genetic risk factors predisposing to psoriasis through genome-wide association studies (GWAS), with 41 susceptibility loci identified to date. The clinical importance of these findings is underscored by the fact that several risk loci point to pathways and molecules already targeted for the treatment of psoriasis. More importantly, the GWAS results have the potential to identify previously unappreciated pathways, which may be critical in the disease pathogenesis and therefore ideal therapeutic targets. One of these risk variants is located within the IL13 gene, but the role of IL 13 in psoriasis pathogenesis is mostly unknown. However, several lines of evidence, including our own preliminary data, point towards a major role for IL-13 in psoriasis, setting the stage for our hypothesis that IL-13 has a pro-inflammatory role in the pathogenesis of psoriasis by potentiating Th1 and Th17 induced skin inflammation. The objective of this proposal is to define the pathogenic role of IL-13 in psoriasis, elucidate the critical pathways and mechanisms involved, and assess the impact of the psoriasis-associated IL13 rs20541 risk variant on inflammation in psoriatic skin. This project will provide new data on an unappreciated and understudied inflammatory pathway in the pathogenesis of psoriasis, it will assess the potential of targeting IL-13 or its receptor system in psoriasis, and ultimately lead the way towards more effective treatments for patients with this chronic, and often, devastating disease.